QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of abarelix and panobinostat. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for abarelix, when combined with panobinostat (100%). We do not expect any change in exposure for panobinostat, when combined with abarelix (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
The bioavailability of abarelix is unknown. The terminal half-life [ t12 ] is rather long at 316.8 hours and constant plasma levels [ Css ] are only reached after more than 1267.2 hours. The protein binding [ Pb ] is 97.5% strong. The metabolism via cytochromes is currently still being worked on.
Panobinostat has a low oral bioavailability [ F ] of 21%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather long at 37 hours and constant plasma levels [ Css ] are only reached after more than 148 hours. The protein binding [ Pb ] is moderately strong at 90%. Since the substance has a low hepatic extraction rate of 0.24, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism takes place via CYP2C19, CYP2D6 and CYP3A4, among others and the active transport takes place partly via PGP, UGT1A1 and UGT1A9.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither abarelix nor panobinostat increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither abarelix nor panobinostat increase anticholinergic activity.
QT time prolongation
Rating: In combination, abarelix and panobinostat can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||aba||pan|
|Myocardial infarction||4.0 %||n.a.||4.0|
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: No Abstract available
Abstract: Panobinostat (Farydak) is an orally active hydroxamic acid-derived histone deacetylase inhibitor used for the treatment of relapsed or refractory multiple myeloma. Based on recombinant cytochrome P450 (P450) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was mediated primarily by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also an in vitro reversible and time-dependent inhibitor of CYP3A4/5 and a reversible inhibitor of CYP2D6 and CYP2C19. Based on a previous clinical drug-drug interaction study with ketoconazole (KTZ), the contribution of CYP3A4 in vivo was estimated to be ∼40%. Using clinical pharmacokinetic (PK) data from several trials, including the KTZ drug-drug interaction (DDI) study, a physiologically based pharmacokinetic (PBPK) model was built to predict panobinostat PK after single and multiple doses (within 2-fold of observed values for most trials) and the clinical DDI with KTZ (predicted and observed area under the curve ratios of 1.8). The model was then applied to predict the drug interaction with the strong CYP3A4 inducer rifampin (RIF) and the sensitive CYP3A4 substrate midazolam (MDZ) in lieu of clinical trials. Panobinostat exposure was predicted to decrease in the presence of RIF (65%) and inconsequentially increase MDZ exposure (4%). Additionally, PBPK modeling was used to examine the effects of stomach pH on the absorption of panobinostat in humans and determined that absorption of panobinostat is not expected to be affected by increases in stomach pH. The results from these studies were incorporated into the Food and Drug Administration-approved product label, providing guidance for panobinostat dosing recommendations when it is combined with other drugs.